ARO 2004 659

1. Possible Interaction between KCNA1 Genotype and Aging on Auditory Spatial Discrimination in the Mouse Paul D. Allen, Peter J. Rivoli, James R. Ison Department of Brain & Cognitive Sciences, University of Rochester, Rochester, NY ARO 2004 659 D(+/-,+/+) Auditory Spatial Discrimination does not appear to be poorer in KCNA1 +/- than +/+ mice with increasing age Interpretive Rule of Thumb: Rd’(difference from control) > 0.6 corresponds to ~P < 0.05 i.e. On 3-D surface plots on the left, orange and red show regions that are on average, for each individual, significantly inhibited by the change in spatial location For a given ISI, Rd’ scales with angle and is reduced in old age Introduction +/- 180° and 45° for each genotype vs. age +/+ Low-threshold K+ conductances underpin temporal processing and control synchrony in neurons of the auditory brainstem. The Kv1.1 channel is strongly expressed in the MNTB, a nucleus involved in ILD processing. We have previously demonstrated that mice lacking the KCNA1 gene, which codes for the Kv1.1 channel, have deficits in auditory spatial discrimination using a novel behavioral task based on pre-pulse inhibition of startle. We have also shown that the same behavioral task reveals progressive degradation of auditory spatial discrimination from 3 to 24 months of age in the CBA/CaJ mouse. In the current study we test the hypothesis that there is an interaction between genotype and age in KCNA1 +/+ and +/- mice in auditory spatial discrimination, specifically that the heterozygote mice, with only one copy of the gene, will show stronger age related declines than their wild-type littermates. 4-8 mo ISI = 50 ms ISI = 50 ms 9-16 mo • KCNA1 +/- mice do not appear to show poorer spatial discrimination than their +/+ littermates • In fact, the effect of aging on spatial acuity may be stronger in the +/+ than +/- mice, but is still less pronounced than previously observed in the CBA/CaJ mouse Methods • Subjects: C3HeB/FeJ-Kcna1tm1Tem mice • 4-8 months (18 +/-, 13 +/+) • 9-16 months (28 +/-, 24 +/+) • 17-25 months (19 +/-, 22 +/+) • 27-30 months (5 +/-, 5 +/+) • Mice held in acoustically transparent wire cage mounted to a platform and accelerometer • Startle eliciting stimulus (ES) delivered overhead (120dB SPL, 15 ms broadband noise burst) • Startle response recorded from accelerometer (RMS 100ms window, post-ES) • Spectrally-matched high-frequency speakers (TDT ES1) located 45cm from the mouse head • Angular separations: 180, 90, 45, 22.5, or 7° • Cage oriented with head facing mid-line of the two speakers • Continuous broadband noise (60 dB SPL, 1-50kHz) presented from one speaker (min 15s, ave 20s) • Prepulse is noise-swap between speakers at set inter-stimulus interval (ISI) prior to ES • ISI conditions: 1, 2, 5, 10, 20, 30, 40, 50, 60, 100, 150, 200, 300 ms, two no-prepulse controls, and a no-startle, no-swap activity control • Speaker angle is fixed in each session (counterbalanced design) with 11 presentations of each condition, block randomized • Inhibition calculated relative to no-prepulse controls (responses to1st presentations excluded) • C3H mice may live longer than CBA mice, and have only mild hearing loss (~20 dB) at 26 months of age • No differences in ABR thresholds across genotype • These mice have good and very similar temporal acuity as measured with behavioral and electrophysiological gap detection (Allen et al., and Ison et al., ARO 2002) • SAM encoding in the CN shows some differences between young KCNA1 +/+ and +/-, but not in the IC (Schmuck et al. # 900 at this meeting) 17-25 mo • We showed previously that KCNA1 -/- mice have a deficit in auditory spatial acuity • Increased jitter of onset latencies in the MNTB (Kopp-Scheinpflug et al, 2003) may disrupt ILD sensitivity in the LSO e.g. via corruption of the time-intensity trading mechanism • No deficit found here in KCNA1 +/- mice, even though they have only half as much Kv1.1 as the +/+ • Could compensation in the +/- impart resistance to the aging-related decline of spatial acuity? • These data indicate that a single copy of the KCNA1 gene is sufficient for normal spatial acuity well into old age, but direct measurements of K+ channel expression as a function of age are required in order to determine the molecular mechanisms underpinning this process. 27-30 mo 90° for each Age: Genotypes and their differences Supported by NIA Grant #AG09524 and The Schmitt Program on Integrative Brain Research